Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

Behary, J; Raposo, AE; Amorim, NML; Zheng, H; Gong, L; McGovern, E; Chen, J; Liu, K; Beretov, J; Theocharous, C; Jackson, MT; Seet-Lee, J; McCaughan, GW; El-Omar, EM; Zekry, A

Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

Behary, J Raposo, AE Amorim, NML Zheng, H Gong, L McGovern, E Chen, J Liu, K Beretov, J Theocharous, C Jackson, MT Seet-Lee, J McCaughan, GW El-Omar, EM Zekry, A

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Publisher:: BioMed Central
Publication Type:: Journal Article
Citation:: BMC Microbiology, 2021, 21, (1), pp. 1-15
Issue Date:: 2021-04-15

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Field	Value	Language
dc.contributor.author	Behary, J
dc.contributor.author	Raposo, AE
dc.contributor.author	Amorim, NML
dc.contributor.author	Zheng, H
dc.contributor.author	Gong, L
dc.contributor.author	McGovern, E
dc.contributor.author	Chen, J
dc.contributor.author	Liu, K
dc.contributor.author	Beretov, J
dc.contributor.author	Theocharous, C
dc.contributor.author	Jackson, MT
dc.contributor.author	Seet-Lee, J
dc.contributor.author	McCaughan, GW
dc.contributor.author	El-Omar, EM
dc.contributor.author	Zekry, A
dc.date.accessioned	2022-03-15T00:44:51Z
dc.date.available	2021-03-31
dc.date.available	2022-03-15T00:44:51Z
dc.date.issued	2021-04-15
dc.identifier.citation	BMC Microbiology, 2021, 21, (1), pp. 1-15
dc.identifier.issn	1471-2180
dc.identifier.issn	1471-2180
dc.identifier.uri	http://hdl.handle.net/10453/155230
dc.description.abstract	BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.
dc.language	eng
dc.publisher	BioMed Central
dc.relation.ispartof	BMC Microbiology
dc.relation.isbasedon	10.1186/s12866-021-02171-9
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	06 Biological Sciences, 07 Agricultural and Veterinary Sciences, 11 Medical and Health Sciences
dc.subject.classification	Microbiology
dc.subject.mesh	Animals
dc.subject.mesh	ATP Binding Cassette Transporter, Subfamily B
dc.subject.mesh	Carcinoma, Hepatocellular
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Dysbiosis
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Inflammation
dc.subject.mesh	Liver Neoplasms
dc.subject.mesh	Mice
dc.subject.mesh	Time
dc.subject.mesh	ATP Binding Cassette Transporter, Subfamily B
dc.subject.mesh	Animals
dc.subject.mesh	Carcinoma, Hepatocellular
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Dysbiosis
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Inflammation
dc.subject.mesh	Liver Neoplasms
dc.subject.mesh	Mice
dc.subject.mesh	Time
dc.title	Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.
dc.type	Journal Article
utslib.citation.volume	21
utslib.location.activity	England
utslib.for	06 Biological Sciences
utslib.for	07 Agricultural and Veterinary Sciences
utslib.for	11 Medical and Health Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-03-15T00:44:50Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	21
utslib.citation.issue	1

Abstract:

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

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http://hdl.handle.net/10453/155230